Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Aoto Hospital, Department of Internal Medicine, Jikei University, Tokyo, Japan.
Mol Cell Biochem. 2004 Aug;263(1):11-20. doi: 10.1023/B:MCBI.0000041844.24424.35.
Earlier studies have revealed an improvement of cardiac function in animals with congestive heart failure (CHF) due to myocardial infarction (MI) by treatment with angiotensin converting enzyme (ACE) inhibitors. Since heart failure is also associated with attenuated responses to catecholamines, we examined the effects of imidapril, an ACE inhibitor, on the β-adrenoceptor (β-AR) signal transduction in the failing heart. Heart failure in rats was induced by occluding the coronary artery, and 3 weeks later the animals were treated with 1 mg/(kg·day) (orally) imidapril for 4 weeks. The animals were assessed for their left ventricular function and inotropic responses to isoproterenol. Cardiomyocytes and crude membranes were isolated from the non-ischemic viable left ventricle and examined for the intracellular concentration of Ca(2+) [Ca(2+)]i and β-ARs as well as adenylyl cyclase (AC) activity, respectively. Animals with heart failure exhibited depressions in ventricular function and positive inotropic response to isoproterenol as well as isoproterenol-induced increase in [Ca(2+)]i in cardiomyocytes; these changes were attenuated by imidapril treatment. Both β1-AR receptor density and isoproterenol-stimulated AC activity were decreased in the failing heart and these alterations were prevented by imidapril treatment. Alterations in cardiac function, positive inotropic effect of isoproterenol, β1-AR density and isoproterenol-stimulated AC activity in the failing heart were also attenuated by treatment with another ACE inhibitor, enalapril and an angiotensin II receptor antagonist, losartan. The results indicate that imidapril not only attenuates cardiac dysfunction but also prevents changes in β-AR signal transduction in CHF due to MI. These beneficial effects are similar to those of enalapril or losartan and thus appear to be due to blockade of the renin-angiotensin system. (Mol Cell Biochem 263: 11-20, 2004).
早期的研究已经揭示，由于心肌梗塞（MI）导致充血性心力衰竭（CHF）的动物，通过血管紧张素转换酶（ACE）抑制剂的治疗，心脏功能得到改善。由于心力衰竭也与儿茶酚胺反应减弱有关，我们研究了 ACE 抑制剂依那普利对衰竭心脏中β-肾上腺素能受体（β-AR）信号转导的影响。通过阻塞冠状动脉诱导大鼠心力衰竭，3 周后，动物用 1mg/（kg·天）（口服）依那普利治疗 4 周。评估动物的左心室功能和对异丙肾上腺素的变力反应。从非缺血存活的左心室分离心肌细胞和粗膜，并分别检查细胞内 Ca(2+)浓度[Ca(2+)]i和β-AR 以及腺苷酸环化酶（AC）活性。心力衰竭动物表现出心室功能降低和对异丙肾上腺素的正性变力反应，以及异丙肾上腺素诱导的心肌细胞[Ca(2+)]i增加；这些变化通过依那普利治疗得到缓解。衰竭心脏中β1-AR 受体密度和异丙肾上腺素刺激的 AC 活性降低，这些改变通过依那普利治疗得到预防。心力衰竭心脏中的心脏功能改变、异丙肾上腺素的正性变力作用、β1-AR 密度和异丙肾上腺素刺激的 AC 活性也通过另一种 ACE 抑制剂依那普利和血管紧张素 II 受体拮抗剂洛沙坦的治疗得到缓解。结果表明，依那普利不仅减轻心脏功能障碍，而且预防 MI 导致的 CHF 中β-AR 信号转导的变化。这些有益作用与依那普利或洛沙坦相似，因此似乎是由于肾素-血管紧张素系统的阻断。（Mol Cell Biochem 263: 11-20, 2004）。
